1-171784166-T-A

Variant names:

• chr1-171784166-T-A
• NM_015935.5:c.580T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015935.5(METTL13):​c.580T>A​(p.Leu194Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: METTL13 NM_015935.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.181
• Publications: 0 publications found

Genes affected

METTL13 (HGNC:24248): (methyltransferase 13, eEF1A N-terminus and K55) Predicted to enable methyltransferase activity. Involved in negative regulation of cell cycle G1/S phase transition and negative regulation of transcription by RNA polymerase II. Predicted to be located in mitochondrion and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06533587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL13	NM_015935.5	c.580T>A	p.Leu194Met	missense_variant	Exon 2 of 8	ENST00000361735.4	NP_057019.3
METTL13	NM_014955.3	c.322T>A	p.Leu108Met	missense_variant	Exon 2 of 8		NP_055770.1
METTL13	NM_001007239.2	c.453+127T>A		intron_variant	Intron 2 of 7		NP_001007240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL13	ENST00000361735.4	c.580T>A	p.Leu194Met	missense_variant	Exon 2 of 8	1	NM_015935.5	ENSP00000354920.3
METTL13	ENST00000367737.9	c.453+127T>A		intron_variant	Intron 2 of 7	1		ENSP00000356711.5
METTL13	ENST00000362019.7	c.322T>A	p.Leu108Met	missense_variant	Exon 2 of 8	2		ENSP00000355393.3
METTL13	ENST00000485629.1	n.565+127T>A		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.580T>A (p.L194M) alteration is located in exon 2 (coding exon 2) of the METTL13 gene. This alteration results from a T to A substitution at nucleotide position 580, causing the leucine (L) at amino acid position 194 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.013	.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
PhyloP100		-0.18
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.22	N;N
REVEL	Benign	0.0070
Sift	Benign	0.28	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.29	.;B
Vest4		0.23
MutPred		0.28		.;Loss of helix (P = 0.079);
MVP		0.19
MPC		0.21
ClinPred		0.052	T
GERP RS		0.048
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.18
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr1-171753306;